title: Tumor-derived lactate modifies antitumor immune response: effect on myeloid-derived suppressor cells and NK cells.
abstract: In this study, we explore the hypothesis that enhanced production of lactate by tumor cells, because of high glycolytic activity, results in inhibition of host immune response to tumor cells. Lactate dehydrogenase-A (LDH-A), responsible for conversion of pyruvate to lactate, is highly expressed in tumor cells. Lentiviral vector-mediated LDH-A short hairpin RNA knockdown Pan02 pancreatic cancer cells injected in C57BL/6 mice developed smaller tumors than mice injected with Pan02 cells. A decrease occurred in the frequency of myeloid-derived suppressor cells (MDSCs) in the spleens of mice carrying LDH-A-depleted tumors. NK cells from LDH-A-depleted tumors had improved cytolytic function. Exogenous lactate increased the frequency of MDSCs generated from mouse bone marrow cells with GM-CSF and IL-6 in vitro. Lactate pretreatment of NK cells in vitro inhibited cytolytic function of both human and mouse NK cells. This reduction of NK cytotoxic activity was accompanied by lower expression of perforin and granzyme in NK cells. The expression of NKp46 was decreased in lactate-treated NK cells. These studies strongly suggest that tumor-derived lactate inhibits NK cell function via direct inhibition of cytolytic function as well as indirectly by increasing the numbers of MDSCs that inhibit NK cytotoxicity. Depletion of glucose levels using a ketogenic diet to lower lactate production by glycolytic tumors resulted in smaller tumors, decreased MDSC frequency, and improved antitumor immune response. These studies provide evidence for an immunosuppressive role of tumor-derived lactate in inhibiting innate immune response against developing tumors via regulation of MDSC and NK cell activity.
authors.affiliation: Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Zaheed
authors.initials: Z
authors.lastname: Husain
authors.forename: Yannu
authors.initials: Y
authors.lastname: Huang
authors.forename: Pankaj
authors.initials: P
authors.lastname: Seth
authors.forename: Vikas P
authors.initials: VP
authors.lastname: Sukhatme
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D005260:Female; D005947:Glucose / Q000096:biosynthesis; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D053804:Granzymes / Q000096:biosynthesis; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000080864:Lactate Dehydrogenase 5; D019344:Lactic Acid / Q000378:metabolism* / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000096:biosynthesis; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054353:Perforin / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D013154:Spleen / Q000276:immunology; D019139:Tumor Escape
chemical_list: D000950:Antigens, Ly; D015850:Interleukin-6; D007527:Isoenzymes; D055627:Natural Cytotoxicity Triggering Receptor 1; C118384:Ncr1 protein, mouse; D034741:RNA, Small Interfering; D054353:Perforin; D019344:Lactic Acid; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D053804:Granzymes; D005947:Glucose